1. Field
The present invention relates to lipase inhibiting compositions having reduced food dependency and decreased formation of free oil.
2. Description
Lipase inhibitors are well known in the art and include lipstatin and orlistat. The latter is also known as tetrahydrolipstatin or THL and is derived from a natural product excreted by Streptomyces toxytricini. This class of compounds was found to exhibit in vitro as well as in vivo activity against various, lipases, such as lingual lipase, pancreatic lipase, gastric lipase, and carboxylester lipase. Its use for the control or prevention of obesity and hyperlipidemia is described, for instance, in U.S. Pat. No. 4,598,089.
Orlistat is currently administered at doses of 120 mg per meal and dosing is independent of the body mass of the human subject. Orlistat acts locally in the gastrointestinal (“GI”) tract and prevents lipase from digesting triglycerides and thus inhibits the formation of absorbable lipid degradation products. For this reason, systemic availability of the lipase inhibitors is not required and, instead, local residence in the GI tract is the preferred mode of delivery.
Lipase inhibitor compositions currently administered inhibit around 30% of fat absorption after consumption of a mixed meal; increasing the concentrations of lipase inhibitors in the pharmaceutical composition does not increase its clinical efficacy and/or potency while the intensity of local side effects increases.
Anal leakage of oil (oily spotting) is an adverse effect, which is occasionally observed by patients treated with lipase inhibitors. This phenomenon reflects physical separation of some liquid unabsorbed dietary fat from the bulk of solids in the lower large intestine.
U.S. Pat. No. 5,447,953 discloses that by combining a lipase inhibitor with substantial amounts of water insoluble crude fibers, the inhibiting effect on fat absorption can be increased. Patent publication WO 00/09123 discloses that by combining a lipase inhibitor such as orlistat with low amounts of chitosan or a derivative or a salt thereof, the phenomenon of anal leakage of oil can be reduced.
International Patent Application WO 01/19378 discloses solid lipid formulations for lipase inhibitors useful to reduce or prevent fat excretion and unwanted formation of free oil. It has been found that a higher efficacy (high fat excretion) can be combined with a lowering of unwanted side effects, e.g. free oil. Recently it has been recognized that the efficacy of lipase inhibitors may depend strongly on the kind of the ingested food. A high efficacy have been found with meals composed of French fries, sausages and hamburgers, while lower efficacy was observed for cheese and other dairy products. Strong food dependency of the formulation efficacy is an unwanted phenomena, because either the formulation is overdosed in susceptible diets (with the consequence of free oil formation) or not active in less susceptible diets. Therefore, the decrease of the food dependency is a prerequisite to realize scenarios with a low dosage of the inhibitor, a high efficacy and less fewer side effects.
Surprisingly, the subject inventors discovered that a certain sucrose fatty acid ester subgroup can increase the activities of lipase inhibitors, decrease the food dependency and decreasing the formation of free oil.